We struggle to understand what to do about our kidney cancer, but first must exactly WHICH kidney cancer we have. Frankly, even the doctors are never too sure, and outcomes for patients with the “same” cancer varied widely. No ready explanation was available, in those bad old days.

Treatment decisions were easy, but not effective for most, when every kidney cancer patient was treated the same. Patients had surgery and were sent home. Those with smaller tumors, under about 2 inches, had little or no follow up. Those with larger tumors might be monitored more frequently. Mets might emerge, and maybe more surgery would follow, but no meds were available until 1992 when high dose interleukin was approved.

Patients who presented with metastatic disease were not even offered surgery, being told that there no value to removing the primary! An ongoing “controversy” was whether there was value in a nephrectomy when mets were found. Too bad, so sad. (If your doctor is telling you that last bit, you need a new doctor. Now.)

Then came the recognition that there were different kidney cancers, variants and subtypes, all based on the look under the microscope. Conventional kidney cancer became known at clear cell, and a mix of new subtypes were named. We now hear of clear cell, papillary type I and type II, chromophobe and more. Sarcomatoid RCC can arise from any of these types, confusing things and reflecting a more aggressive course for the patient. Most are sporadic, out of the blue, but others have an inherited component. Again, making things trickier yet!

Ironically, the trials in the late 80s of high dose interleukin which led to the first FDA-approved treatment, included all the above types. The relatively low response rate in this trial may have been due to the rarer RCC types, unlikely to respond. This minimized the use of HD IL2, perhaps to the detriment of many patients. The targeted therapy studies often excluded the rarer types, hoping to boost response in a more limited group. Few trials really test agents appropriate for the non-clear cell types, so the guessing game for them is really the norm.

With that background, there was still wide variation in the outcomes for clear cell RCC patients. Some patients with small tumors, found at an early stage, can have very poor response to treatment. Many such patients have long-term survival, easily over 10 years, while others who “seem” similar, succumb to their disease quickly.

Why is this the case? Short term survival vs long term survival, aggressive appearance of mets vs slow-growing, good response to treatment vs minimal response? Why would the same disease be so different?

Easy answer. It is not the same disease. Clear cell RCC, that so-called conventional type, maybe 75% of all the kidney cancers, is not really one disease. Clear cell may be subdivided into four separate types, each with its own survival pattern–and all due to its early genetic drivers. Researchers have been able to sort out the genes, compare the mutations, deficient or over-expressed, and find them in tumors of patients who were treated and followed over many years.

Just as there is no magic bullet, no one medicine that fixes everything, there also seems to be no one poison bullet. It is not just one thing that goes wrong, one nasty gene breaking the DNA rules, but a combination. And there will be more combinations. This is like the typical disaster stories, where it is not just one thing that goes wrong, but a series of events and changes. Each one of the series might not create a problem, but in combination and with the right timing, there is a perfect storm–the very aggressive tumor.

Without getting too technical, clear cell RCCs can have a mix of genes that mutate. Recent studies have shown that two genes in particular, BAP1 and PBRM1 can either be sufficient (or competent or positive) or they can be deficient in their expression. There are four possible combinations, positive for both genes BAP1 + and PBRM1+, negative for both genes BAP1- and PBRM-, and combinations with the BAP1+ and PBRM-, and the reverse, BAP- and PBRM+.

Why does this matter for the study patients? All of them had localized disease at the time they were diagnosed and all were clear cell patients of similar age. BAP1 was mutated/inactivated/deficient in about 15% of these patients, and that mutation was associated with high nuclear grade, or a more aggressive type of tumor.

About 50% of clear cell patients had the PBRM1- tumors. Others had a mix of one gene positive and the other negative. Mutations of BAP1- and PBRM1- were rarely found together, but that combination predicted poor survival, in one study of just 2.1 years. Having just the BAP1- had an overall survival of 4.6 years median, while the deficiency of PBRM1 (-) had an overall survival of 10.6 years.

This shows that clear cell RCC is really not one disease type, but four. Most importantly for patients is the knowledge that these varying mutations may respond to different medications. Also, these mutational differences can be seen in immunohistochemical or pathology tests, which can give greater guidance to treating physicians.

Coming soon is another lectures by Dr. Brugarolas, so watch this space.

Once you reach a ‘certain’ age, you are horrified, but not surprised to get a cancer diagnosis, or hear about it in a loved one. That same cancer in a young person is even more horrifying, we instinctively know.

Most kidney cancers (and there are more types than we previously knew) are found in people in their 60s and 70s. Bad enough, but a cancer called by the same name and found in a younger person is often a very different cancer, with a very different prognosis.

Some new research recognizes that special attention should be paid to those RCCs found in patients 46 years of age and younger. Why is this?

The quick answer is that this may represent a more aggressive kidney cancer and/or be of a familial or hereditary nature. That important distinction has researchers strongly recommending that young patients be referred for genetic testing. This can explain those special risks and create more appropriate treatment plans, and alert other family members as to special monitoring. Critically it may change the approach to any removal of the kidney and/or tumor.

Typically a small renal mass might be monitored or removed by either surgery or some laser ablation. If removed, the tumor can be assessed by a pathologist–a look under the microscope.Without a prior biopsy, the ablated tumor will not be examined, and no genetic testing can be done.

BIG HOWEVER HERE: even with a good pathology report, that may tell only what that tumor looks like–not what pushed it to grow, i.e., the genetic drivers. And those genes don’t go away with the tumor, so the risk remains that more tumors will grow, maybe in the second kidney, or in the partially removed kidney. Plus the rest that can happen with cancer…

An 75 year old whose small renal mass is removed will likely function well with one kidney. That same tumor in a 35 year old creates another challenge. If that tumor is driven by familial genes–not just by sheer bad luck–more tumors on the other kidney may be in the works. A partial nephrectomy must be considered. The risk of more tumors emerging in that kidney AND the other kidney is high. The younger patient needs decades of good kidney functioning, but those decades carry the risk of the emergence of more mets.

What else should trigger a genetic testing?

Quick answer: anything that doesn’t look like the senior citizen with a single tumor in one kidney. More officially below:

Early onset of kidney cancer is 46 years or less.

Bilateral (two-sided) or Multifocal (many locations) kidney tumors

Family history of kidney cancer, 1 or more close relative, 2 or more in more distant relatives

Kidney cancer with either a mix of other tumor types roughly related to kidney cancer or with lung cysts or pneumothorax (air leaking out of lung into chest cavity)

Personal or family history of kidney cancer syndromes.

The above list is from Yale School of Medicine, Professor Brian Shuch, who work includes dealing with heredity forms of kidney cancer.

More small renal masses found at an earlier age in more patients, as our imaging techniques improve and more CTs scans are done. Not all will be hereditary, and many will be sporadic or out-of-the-blue kidney cancers. Those are likely due to the sheer chance. Things go wrong as trillions of cells divide and make DNA mistakes along the way. Years of environmental damage may overwhelm the body’s ability to correct those DNA mistakes–i.e., the immune system gets overwhelmed, tricked, tired, etc.

Kidney cancer found at an early age or with the bilateral/multifocal tumors simply must be tested as to it genetic origins. This gives information critical to protect the rest of the kidney(s) and to participate in treatment that is more helpful. Finding an effective treatment will still be a challenge, but proper treatment requires knowing exactly which kidney cancer you have. From there, a real plan can be developed.

Just as I remind all readers to work with an experienced RCC oncologist–not just a surgeon and/or urologist (sorry guys, we need a team)–those who fall into this early and hereditary renal cell carcinoma category must also work with super specialists.

The person to contact at NIH is genetic counselor Lindsay Middelton at (301) 402-7911. She is with the National Cancer Institute’s Urologic Oncology Branch. An introductory link is below to the NCI and two other rare kidney cancer organizations.

Kidney cancer is the focus here, but I can’t resist writing about the empowered and determined lung cancer patients who changed the rules–the NCCN guidelines–in treating their cancer. With this, there is support for treatment for their newly established metastases which was previously lacking. Translation for the patient was, “It’s come back, so just go home. End of story.”

What does this mean for kidney cancer patients, or for others? For that matter what does “oligometastases” mean anyway?

” Oligometastases are defined as 1–5 distant metastases that can be treated by local therapy to achieve long-term survival or cure.”

Earlier, some doctors felt that there was no reason to treat a patient who was initially diagnosed with metastatic disease. If the cancer had already metastasized, nothing that could be done, not even the removal of the primary tumor. Oddly enough, patients often got no treatment and the self-fulfilling prophecy worked again.

We kidney cancer patients know better. (My 10cm tumor and the lungs full of mets would have NOT been treated by many doctors.) Removal of the primary tumor can have real benefit, even when there is no treatment for the metastases.

Similarly, the emergence of mets post-surgery was also seen as a “game over” by many doctors. The “got it all” surgery that was welcome news was suddenly a forgotten phrase. How many sad visits a year or two after of misplaced confidence? Kidney cancer will come back far too often, suddenly emerging near the old tumor or in some of the favored spots. With kidney cancer, that is the lungs, bones, adrenal gland and the brain.

These new mets, generally in the area of the primary, are those oligomets. Hard enough to say, and harder yet to be told that the docs will do nothing–because the guidelines say it is not worth it. That was the situation for non-small cell lung cancer patients with new mets.

But these cancer patients were NOT having that kind of non-help!

They gathered all the data, showed the value of going after these mets and convinced the NCCN to make significant changes in their guidelines. Now doctors and the insurance people cannot deny these treatments on the basis of these guidelines.

Keep in mind that most doctors and insurance companies want to use treatment guidelines based on some acceptable medical standards. One guideline comes from the National Comprehensive Cancer Network. This establishes the working rules for what kind of treatment or monitoring is thought appropriate for any stage of cancer. For example, the treatment for a Stage I tumor is quite different from that of a Stage IV tumor. There are guidelines for shifting to new medications, and for monitoring of primary tumors or mets after surgery.

Since kidney cancer most often metastasizes to the lung, I monitor some of their sites, and was thrilled to see this. Power to the patients, people!

Being diagnosed with kidney cancer is a stunner. Facing surgery and endless, oft unanswered questions changes your life. Patients with small tumors, easily removed, are often told not to worry about it coming back. Of course, there is ALWAYS the possibility that even small “I got it all tumors” can recur. Sadly, the current guidelines fail to catch about 30% of recurrences, using the 2013, 2014 guidelines. These guidelines were from an earlier era, where there were fewer small tumors found, so there was data lacking on long-term follow-up.

We patients ask? “Why not just take the meds that the patients with metastatic disease do? Wouldn’t that prevent it from coming back? If it works to fight the mets, why wouldn’t it prevent new ones from getting a foothold? “

Why not use the meds that they use now against metastatic disease? Why wouldn’t that work? Have they tested that idea?

In February of 2015, a study was released which comparing patient response to 1) sunitinib (Sutent),2) sorafenib (Nexavar), or 3) placebo (no real medicine). This three-arm study included 1,943 patients who had locally advanced clear cell and non-clear cell histology RCCs. They were thought to be at high-risk for recurrence of their cancer, and might benefit from “adjuvant” therapy. The researchers hoped that they would see a 25% improvement in time to recurrence of disease with the meds vs no meds.. That would means that the typical 5.8 years median Disease Free Survival (DFS) would go to 7.7 years.

Sadly, there was no benefit to taking the active drugs compared to the placebo. More sad is that the patients had side effects associated with the drug, referred to as “adverse events”. In fact, many dropped out of the active agent arms into the placebo arm, certainly knowing that the med they were taking were anti-cancer meds. Those “adverse events”, severe fatigue, hypertension or hand-foot reactions, were observed in those taking the active agents and rarely in the placebo patients.

The median time on the drugs was 8 months. That means half the patients were on drugs more than 8 months and half were on the drugs less than 8 months. Even those patients starting with lower doses of the drugs fared worse than the placebo group.

Despite taking the medications and enduring the side effects, the recurrence was about the same. With medication or without, these patients, as groups, did the same. Those taking the meds had Disease Free Survival of 5.6 or 5.7 years, similar to those not taking any real meds. There was no real added benefit to these patients. Certainly the quality of the life was affected by the side effects, and the constant reminder of the spectre of more cancer.

What can patients learn from this study?

The fear of recurrence is real. After all, the expected time until the disease progressed (love using that term for cancer!), was about 5 1/2 years. These patients were carefully monitored with CTs on a regular basis, which caught their recurrences as soon as possible. Had they not been in this trial, it is reasonable to expect that many would not have received those scans and not know of the recurrence as it happened.

The reality is that the typical patient may or may not continue to be monitored. Even those who passed the 5 1/2 year mark without recurrence may not realize that RCC can come back. Again, 30% of recurrences in small, non-metastatic disease are not caught. One can assume that the higher risk group in this trial would also be at risk for that level of recurrence.

Take-home message: At present, nothing has been shown to prevent recurrence of this locally advanced disease. Even the non-metastatic small tumors that have sent out invisible “wanna-be mets”, and no one can yet guess who is at the most risk.

The best approach is to monitor yourself and your general health and to demand CT scans, especially in the lungs, where metastatic RCC is most likely to start. That does NOT mean an x-ray, as those mets would have to be about 1/4″ in order to be seen. My own lung mets were under that size when first found, but there were hundreds of them, and they grew quickly. Not visible on an x-ray, but growing every day.

Despite the disappointing study above, the ASSURE study, more clinical trials are recruiting patients for similar studies using drugs that have already been shown to be less active than those in the ASSURE study. I would be cautious in getting into such a trial, and would spend my energies seeing that my monitoring is extended at least until 10 years past my surgery–even with those “got it all” primary tumors.

No one wants to look for extra trouble after having been diagnosed with kidney cancer, even if the tumor is small. Horrified already by the cancer, it is more horrifying to realize that there are no guarantees, even when told by a reassuring surgeon that he “got it all”. The reality is that even small masses can have sent out cells to other sites, in the rest of the kidney, should it have remained, or to distant sites. (In cancer, ‘distant’ is never as distant as it should be, as that means there is cancer in some area away from the primary tumor. Could be lungs, bones or brain, sorry to say.) So now what do you do? And what can you do?

With the more sensitive imaging techniques, x ray, ultrasound, CT scans, and MRIs, more smaller tumors are being found. The hope is that finding and removing them will be completely curative, and there are plenty of papers to say that is the case. But is it really true? Unfortunately, finding tumors sooner also means that they may need to be “followed” or monitored longer than has been done in the past.

Consider the situation where a tumor about 2 inches in size is found, and scheduled to be monitored for five years. Though with no symptoms, the patient gets that “last” scan, only to find a newly visible met. Not visible at the year four scan, it may have been slowly growing , unseen for 2-3 years There may be further monitoring, and perhaps a surgery to remove it or one of the newer drugs is given, in hopes of downsizing or stabilizing the met. Happily the five year plan worked to catch this one.

Had that same tumor been found two years earlier, maybe just 1 inch in size, and monitored for five years, no further met would have been found. The monitoring may well stop at five years, while the slow-growing met continues to grow, still not visible to the scan. It may only be symptoms at year 7 or 8 which brings the patient back to the doctor, and this time with larger and perhaps more mets, not visible at the year five.

Older monitoring schedules were based on the low and grim expectations for kidney cancer patients. There was little thought to tracking patients for more than five years. After five years there weren’t that many patients!

With earlier detection, and more treatment options, now is the time to review monitoring to capture recurrent disease, which we patient call, “It came back.”

We do look to the five year mark, thrilled to have made it, especially so if we have been cancer-free. Not quite like graduation, but more like the beginning of summer vacation. But we (and our doctors) must be reminded to keep checking back in with the school principal/CT scan. We need to be sure no leftover bunch of cancer cells have become a measurable metastasis.

Let’s talk about size, as it really matters. So does the attitude–aggressive or indolent–of the cells of even the tiniest tumors. Some may well have sent out their own colonists, looking for areas to set up housekeeping. Clear cell RCC most often goes to the lungs, so lungs deserve close attention. X-rays can only see a pea-sized met, about 1 centimeter in size, so a CT scan, with and without contrast is best to find new mets.

What are the chances of finding mets, either sooner or later, with a small renal mass? Lots of stats and some terminology here, so take notes as needed. Better yet, grab your own post-surgery report, or the imaging reports so you know where you stand.

Measuring Small Renal Masses

Primary kidney tumors are measured on a T (for primary Tumor) scale that runs from TX–no primary tumor found, to T4, which is any tumor 10cm or larger(There are 2.54cm to the inch, so that is 10cm/2.54cm=3.9 inches. Think four inches, and remember that it can be shaped like a potato, not a ball or a pancake. They can be measured at a different spots in different scans. That is why measurements can vary from report to report.

T1 tumors are divided into T1a and T1b, and are limited to the kidney. T1a tumors can be up to 4cm in size, using the largest dimension. Officially this is the small renal mass. Volume counts in the real world, but a 4cm x 2cm will be described as the same size as a 4cm x 4cm tumor.

Tumors which are named at T1b size are still limited to the tumor, but can be up to 7cm in the longest dimension, so about 2 3/4 inches long. The officially small renal masses No longer described as small, it SOUNDS small by the name. Assuming that there is no other evidence of cancer outside these masses, this is Stage I cancer. Given the grade of the biopsied tumor, it may be considered to be low or high grade, which is a measure of the aggressive nature of the tumor.

Tumors in the T2 range are also divided into T2a and T2b. These are still limited to the kidney, with the division at the 7cm mark. T2a tumors are over 7 centimeters (think 3+ inches), and up to 10 centimeters, nearly 4 inches

Though I was lucky to receive good care, after eight precious months working with a specialist trying to figure out why I went from healthy to damned ill, it was more than good medical care that saved my life. Being diagnosed with a terminal illness is terrifying and isolating. I felt alone in a wash of pink ribbons, without anyone who understood my disease process and how to deal with it. Who gets kidney cancer?!

By some internet miracle, and at the depth of my horror at the prognosis I faced, I found ACOR–Association of Cancer Online Resources–now called www.SmartPatients.com. http://www.smartpatients.com/kidney-cancer These were other patients who provided both TLC and education that I so desperately needed. Moderated by intelligent and experienced patients and caregivers who knew what had happened to me. What I did not get was someone telling me that I had gotten sick for failure to buy their supplement or for leading a dissolute life!

I wrote a simple distress call online, that I just had a nephrectomy and was being advised to consider HD IL2 for my countless lung mets. I needed help. Within forty minutes, another patient offered his quick story with the disease, that he was working, in a clinical trial and doing better. He gave me his number and said it was a good time to call. I did call, and found a real person on the other end, who immediately let me know that I was not alone, that other options were emerging from the research, that my doctor was considered to be excellent and so on. Not only this call, a clear signal that I was not alone, but he gave me his cell number, his work number and his pager. “Call me anytime you need to talk.” With that, my head cleared every so slightly, and I began my journey to this world, one which has lasted nearly ten years. And it has led to you.

Through www.SmartPatients.com I have come to offer my own knowledge to others, and hope you will find this a valuable resource as well. You will be welcome, and given tools to make you more capable of dealing with kidney cancer. Other cancers have similar groups, of course, as we all need to be SmartPatients.

My first foray into the world of “patient” began the day I was diagnosed with kidney cancer. All my other visits with the doctor, my hospitalizations to have children, and even the odd time I received IVs of blood never had turned me into a patient. To be deemed a patient was for other people, for those who were sick, or chronically ill.

That was never me until a wish for cosmetic eye surgery led me to get a blood test and the report of extremely low red blood cell count, a hemoglobin measure. Mostly aggravated that low reading would hinder my plans to have new eyelids, I assumed my approaching menopause had shifted things a bit for me. Get “re-calibrated” with some blood, be a bit smarter about eating other than M&Ms for lunch, and all would be well.

Well didn’t happen that way. Being told by my GP to go to the ER to be admitted to test for my low red blood cell count was more an annoyance, and bewildering. The GP told me to be careful driving, as I could “bleed out”, were I in an accident. Had I taken him seriously, I might have been better off, but who wants to become a patient?

Three pints of blood, a colonoscopy, an endoscopy and a doctor assigned to me by the hospital later, I was sent home with a packet of iron pills, and reminder to eat very well, especially protein. More liver pate and red meat, and fewer M&Ms, and an improved diet would fix it all, I was told.

Months and more tests later, looking less and less healthy, losing weight, being polite to the doctor, being on time and starting to fade away, I did not know that I was dying. As I could later determine from the doctor’s notes, he thought I was an alcoholic in need of a liver biopsy to “confirm the cirrhosis”. That biopsy required an ultrasound, and the race was on.

The ultrasound tech was chatty and friendly, until a sweep of her wand across my lower right belly. She turned herself and her screen away from me and stopped talking. Knowing the liver was on the left, and her wand was on the right, I had a pretty good idea that the kidney was the new problem area. Of course, my questions went unanswered, but was told that I would have a CT scan later than day. But still no answers.

Still in the flimsy hospital gown, I discussed with my husband what was likely my new kidney cancer diagnosis, and figured I would just get a neat little incision, where they could take out the neat little tumor and I would get on with my neat little life. Off to the CT scan, with more techs discussing me, carefully out of earshot, ignoring my pleas to explain what had been found. “You doctor will talk to you” was the non-response.

But he was pretty non-responsive as well, waiting until late in the evening before telling me what I already knew, that I had a mass on my kidney. Masses don’t belong there, so it must be cancer, but he was unwilling to affirm that. He would find me a urologist the following day, he promised.

That recommendation given without further info, and in light of the frantic internet search, I was not enthusiastic about his recommendations, and especially when the urologist failed to mention any expertise with kidney cancer on his website. Ain’t a good sign, says I, so plan B was to get to the Mayo Clinic.

I had grown up in western North Dakota and had learned that fancy health problems spurred a trip to Rochester, Minnesota. Within a few days, I was in the Mayo Clinic, going through a series of new tests and imaging with the urologist appointment at the end of the day. Try to coordinate that in less than 24 hours, and you will appreciate the miracle of Mayo.

At that appointment, my neat little tumor was now described as a malignant mass, about the size of a softball. It had pushed the kidney up toward the liver, and thus caught the attention of the US technician. Bad enough, I thought, but the subsequent CT had also shown my lower lungs to be full of tiny mets. Mayo’s more thorough CT showed my entire lungs to be filled with tiny white metastases. Not only did I have a huge tumor, my lungs were essentially a tumor colony.

Stunned, and nearly deafened by this news, I struggled to hear the doctor say, “I have a plan for you.” With that hope and that plan, I began to breathe again. And have been doing so for the last 10 1/2 years.

Thanks to so many people at Mayo, including Dr. Brad Leibowich, his staff, the angel nurses, and the Mayo brothers who created this wonderful place.

Trying to explain in a patient- and Peggybrain-friendly way how molecular pathways which go awry and lead to cancer, I kept reading about enzymes and antagonists. With these various genes with their cloning, overexpressions, mutations, and amplifications, and their antagonizing one another into action or inaction, now I antagonized! Go slow on this, marvel at the body’s complexity and remember there is no magic bullet to end cancer. Sorry to all, especially to the newly diagnosed, but this is true.

Molecular Pathways—Or a Network?

The complexity of the dynamic molecular pathways that are essential to our very beings cannot be understated. Researchers are beginning to understand these signaling systems.and no wonder. In a dynamic dance, push cells to divide, to move and to die off, all to support the human organism. When those actions become aberrant, tiny changes can be life-threatening.

“Pathway” is used to explain these interactions in the molecular processing, but it evokes a linear image, direct and orderly. Each chemical reaction may seem to be a stepping stone on that path of cell growth. Missing a step or shifting into another pathway may impact the information sent to the nucleus of the cell. Missteps in this process can lead to unwanted growth, or the path being interrupted completely. But a molecular pathway is anything but simple and predictable.

Pathways may better be described as a string of knots to be loosened or tightened—or both. Each knot is a point where molecular changes may be triggered by chance interactions from outside that string. Those many pathways with their overlapping functions are wadded together, in an intricate spider web. These tangled paths add efficiency as they can create “work-arounds” as needed, supporting the required needs of the system. All such pathways lead, directly or indirectly to the nucleus of cells, and to some function of the cell or larger system.

As those actions cascade down that string, from one knot to the next, they are influenced by other actions and reactions, and can trigger other pathway cascades. The aberrant or misdirected impulses can trigger unintended growth signals, or fail to stop the appropriate death of unnecessary cells (apoptosis=cell death). If something goes wrong, the exquisite and swift balancing act can shift to support a cancer cell. Once that cell has been created, it may evade the inhibiting signals, subvert other processes, create its own support structure and to move to other parts of the body. This may lead to metastases or spread of a cancer to a new site.

One large and complex pathway which can give rise to sporadic tumors and to genetic syndromes is that of the PI3K (phosphoinositide 3-kinase) pathway. Most often it is referred to as the PI3K/AKT/mTOR pathway, a reminder of its wide span of action. It is an especially involved pathway, as per the long name! Studied since the 1980s, the PI3K pathway plays a key role in essential cellular functions. It is fundamentally involved in development of the embryo, and is one of the most commonly activated signaling pathways in cancer.

Mutations can be found in the inherited gene (germline mutations) or sporadically (somatically) as a part of normal growth, aging or environmental causes. Germline mutations make some people more likely to develop a certain cancer, while other people get a similar cancer by sheer chance. By studying germline mutations, researchers gain insight into the sporadic mutation versions of many cancers. Since the PI3K pathway is so fundamental in growth, there is great need to target of this pathway to find relief from the cancer-inducing signals.

Relationship to Receptor Tyrosine Kinases

The PI3K pathway is linked to the large class of Receptor Tyrosine Kinases, (RTKs), and its activation can lead to a wide variety of cancers. The type of those alterations–whether mutations (changes) or amplifications (duplications)—gives rise to different cancers. For example, a mutation of PIK3CA on this pathway is found in 27% of breast cancers, and 17% of urinary tract cancers. Amplifications of that same gene is found in different rates in several lung cancers. Related PIK3CA is found in 53% of squamous cell cancer and just 12% of adenocarcinomas, while the mutation of PIK3CB is expressed in 80% of bladder cancers, and only 5% of breast cancers.

Activation of Pathway

As PI3K becomes activated, whether from PTEN or other growth factors, it subsequently will activate AKT (Protein Kinase B) and then mTOR (mammalian Target of Rapamycin. All play a role in cell proliferation and apoptosis (natural cell death), so any over activation can lead to excessive growth or loss of natural inhibitors. Once cells no longer function under the normal restrictions, they recruit additional growth factors, override immune responses, and proliferate.

Tumor Suppressor PTEN and PI3K

A tumor suppressor PTEN (phosphastase and tensin homolog) can be found on this pathway. This protein is encoded by a gene which is frequently mutated in many cancers. Loss of this tumor suppression activity happens in about 70% of prostate cancers. Coupled with the other alterations in PI3K and its downstream AKT (protein kinase B), the loss of this suppressor can lead to the development, not only of many cancers, but other disorders. Germline (or inherited) mutations in PTEN play a role in, some non-malignant tumors and related syndromes, and possibly some autism spectrum disorders.

Should the PTEN gene mutate and its tumor suppression be limited, changes are triggered along the PI3K pathway. Those mutations can occur in many of the steps along the pathway to the nucleus of the cell. One misstep–an amplification or a mutation–can lead to more such missteps. With those variations, the resulting tumors will have varying incidence of that mutation. An amplification of one element will be found more frequently in certain lung cancers, and rarely in a prostate cancer. Bladder cancer may show overexpression of a related element in 89% of the time, while never exhibit another type of mutation.

All of the elements in this PI3K pathway can contribute to cell proliferation, to cell survival and motility (ability to move) and to angiogenesis (blood vessel development). Agents to target this missteps along the path have been developed, Some act to inhibit in the PI3K subpath, others in the AKT subpath, and several in the mTOR(mammalian target of Rapamycin). These agents are prescribed for cancers as varied as the steps along the pathway.

Therapeutic Agents in Use and Development

The mTOR family of inhibitors includes Temsirolimus (Torisel) and Everolimus (Afinitor), approved for some renal cell, breast and pancreatic cancers. Many others are in development and in trials for a mix of blood and soft tissue tumors.

Upstream from mTOR is the PI3K pathway, so both can be targeted. Currently under study is an inhibitor of the AKT pathway, Perifosine, for the treatment of colorectal cancer and multiple myeloma, in combination with other drugs. Similar drugs are under investigation as they may overcome resistance developed to other drugs.

Genetic Analysis and Treatment Approaches

Multiple genetic alterations these pathways can be found in the tumors or blood of cancer patients. Those alterations may trigger more changes in the primary tumor as it grows. That first kidney tumor can continue to change, following the initial mutation in the first few cancer cells. Billions of cells mutate, evade the immune system response, and respond to the new molecular actions. Thus, new and different cell types may be created. A primary may exhibit certain characteristics, and its metastatic tumors may be quite different. Some tumors may respond to a treatment and nearby tumors will not, as each may have developed in response to different molecular interactions in the same pathway.

It is vital to have a thorough analysis of the tumor’s from several places in the tumor, as well as from any metastases. Only with this can therapeutic agents be chosen to counter the cancer/those cancers. Pathologists may find several different types of cells in one tumor, and in the same tumor find still other unique cells from another tumor sample. The impact of molecular analysis will certainly change treatment, but it must begin with a very sophisticated and thorough gathering of the cellular material deemed to be cancer.

Why don’t the various medications work better for RCC? Why do some patients do well, and others so poorly? Why is it so hard to choose the right medicine?

This lecture explains why patients and doctors must play the guessing game in treatment. It may be the most important lecture in this blog, and provides an explanation as to why RCC cancers behave so differently, even those variants with similar pathologies. (My notes are in italics, like this, added to help with this complex discussion…I hope.)

“I am going to talk to you today about the genetics of kidney cancer and how I believe it is paving the way for the next generation therapies. There are no significant disclosures.What is the problem? This is a problem that we are well aware of some nowadays. We’re using one drug for all patients with kidney cancer. You may imagine that these are all patients with metastatic renal cell carcinoma. But it is a heterogeneous population. Some have the red tumor, some of them the green tumor, and the drug may work with a subset of patients, but it may not work for another subset of patients.(Left half of the slide with the meds not reaching the patients with GREEN tumors.)

We should be evolving to a paradigm where patients with different tumors are treated with different drugs. (Right half of slide shows Drugs A and B going to different subsets of patients.)In the context of renal neoplasms , as you are well aware, we have kidney cancer with clear-cell carcinoma which accounts for the vast majority (75%) of that, and that’s going to be the focus of the first part of the talk.

The work from the Sanger Institute by Andy Futeral and Michael Stratton led to the identification of mutations in the PolyBromo1 gene. Polybromo1, like VHL, the most commonly mutated gene in clear cell renal cell carcinoma, is a two-hit tumor suppressor gene. That means both copies are mutated in tumors. They identified through truncating mutations in approximately 41% of clear-cell RCC. PolyBromo1 encodes BAF 180, which is a component of a nucleosome modeling complex which may regulate, among other processes, transcription.” (Peg & Wikipedia say that transcription is the first step of gene expression, where DNA is copied into RNA, giving instructions. Pretty basic cell info.)

“Work from my laboratory led to the discovery of another gene mutated in RCC, the BAP1 (BRACA1 associated protein-1) gene. Like the BPRM1 and VHL, BAP1 is a two-hit tumor suppressor gene, but it is mutated in only about 15% of sporadic clear-cell RCCs.

This work was done focusing on tumors that were of high grade. Indeed, we found there was a correlation between BAP1 loss and high grade, and also activation of the mTOR1 pathway. BAP1 encodes a nuclear deubiquitinase. Of greatest interest, mutations in BAP1 and BPMR1, we found, are largely mutually exclusive. This is shown this more detailed the next slide.

What you are seeing here are 176 tumors, each in a row. These are tumors that have a deletion in PBMR1, these are tumors with the insertion, this with a point mutation (referencing the various symbols P). All the tumors in blue are tumors that have a mutation. As you can see most of the tumors, we see with PBRM1 mutations do not have mutations in BAP1. (Column 4 has many BAP1 mutations.)

(in last column) Here you have some tumors with mutations in BAP1, and we only identified three tumors that had mutations in both genes. (Very end of column 4) The probability of having mutations in both genes was statistically significant. Based on the individual mutation probability, we would have expected 13 tumors to have both genes. Only three were found, suggesting that BAP1 and BPRM1 mutations are largely mutually exclusive.

We went on to performing a meta-analysis. This is looking at data from that Beijing Genome Institute, at Memorial Sloan-Kettering and this from the TCGA (The Cancer Genome Atlas). As you can see, even though the numbers are small, the numbers of tumors with mutations in both BAP1 and PBRM1 was reduced, compared to the expected number of tumors based on the individual mutation frequency, and the p value was statistically significant.I’m going to go through these and not spend much time, but suffice it to say that that we found that these tumors that have had mutations in BAP1 have a characteristic gene expression signature, and the tumors that have mutations in PBRM1 also have a characteristic gene expression signature. These gene expression signatures do not overlap. These are tumors that have different gene expression patterns and different biology. (Per Peg: this shows that these are biologically different tumors. Notice the different patterns of red and blue below.)

We think this establishes a foundation for the first molecular genetic classification clear-cell RCC. In our series, 55% have mutations in PBRM1, and 15% of the tumors have BAP1, and including 3% have mutations in both. (The balance are wt, wild-type, meaning as it occurred in nature, not mutated.) We also observed that there is a statistically significant correlation between mutations in BAP1 and high grade (tumors), and mutations in PBRM1 in low-grade (tumors).

So that let us to propose the following model. This is a model based on the fact that, very interestingly, VHL, BAP1, and PBRM1 are all located on chromosome 3. In fact, the short-arm of chromosome 3, and this is an area that is deleted in the majority of patients with von Hippel-Lindau-associated renal cell carcinoma, as well as in the majority of sporadic renal cell carcinoma, depicted here in blue. (VHL associated RCC is an inherited type of RCC, not arising from a mutation…but along the same chromosome.)

You can imagine that with a single deletion, the kidney cell is losing, in fact, four copies or one copy of these four different tumor suppressor genes, the BAP1, PBRM1 and VHL.

We have proposed the following model. We believe that renal cell carcinoma, and this is consistent with data from Gerlinger and colleagues, that it begins with an intergenic mutation in the VHL gene. And this is followed by loss of 3p, with a concomitant loss of one copy of all of these tumor suppressor genes. We then think that a mutation in PBRM1 leads to the loss of PBRM1 function, which is a two-hit tumor suppressor gene and low-grade tumors, whereas the mutation in BAP1 is associated with the development of high grade tumors.

REFER to ABOVE PIE CHART re High and Low Grades

This model also predicts that patients with BAP1 and PBRM1 deficient tumors may have different outcomes. So we simply took those patients whose tumors we had analyzed and asked what happens to their outcomes. (The UTSW and TCGA cohorts reference tumors from different institutions. Blue lines are the PBRM1 deficient tumors, and red lines the BAP1 tumors. The lines which fall the quickest show poorer overall survival.)As you can see here (LEFT), we found that patients with PBRM1 deficient tumors had a significant better Overall Survival than those who had BAP1 in their tumors, which had a Hazard Ratio for that of 2.7.

We did a similar analysis with the TCGA cohort, and we found (RIGHT) essentially the same result in the same hazard ratio of 2.8, indicating that BAP1 mutant tumors are associated with worse outcomes in patients. This data has now been reproduced by Hakimi and James Ying at Memorial Sloan Kettering, as well as the TCGA with their own analysis and our colleagues in Japan and Tim Eisen.

There are some limitations of sequencing. We all like next generation sequencing, but it has some limitations. First, it focuses on DNA. Secondly, it uses pooled material. Thirdly, it has reduced sensitivity which is a consequence of contamination by normal cells. In addition, a negative result does not guarantee that there is normal function. There is poor discrimination of subclonal mutations in different cell populations. So as a consequence of using poor material, we cannot tell whether these mutations are found in the same cells or different cells. Typically, it involves fresh frozen samples which are reduced in numbers, and consequently has limited power for doing some analysis.

Interestingly enough, immunohistochemistry (IHC), which we’ve use for a long time is a lot more precise. This is because actually you get information at the cellular level, and you get information about the protein. I mentioned to you that BAP1 is a two-hit tumor suppressor gene, which basically means when it gets mutated, you lose both copies.As you can see here–this is the same series showed before. These are here in blue the tumors that had mutations, in the second column, you can see blue and brown, the results by immunohistochemistry. That is done by IHC. And BAP1 is a nuclear protein, as you can see in these beautiful nuclear staining.

The bottom line is the majority of tumors that had mutations (referencing blue column data points) had lost BAP1. There were two tumors with point mutations where we were able to detect the protein. But there were three additional tumors we could not detect protein, but where there was no protein. If there is no protein, there cannot be functioning.

The rest of the tumors, with one exception, were all positive. So compared to mutation analysis, in fact, there is positive predictive value is better and the negative predictive value is pretty similar.

We have used this immunohistochemisty test in conjunction with the Mayo Clinic, looking at their registry with over 1300 with localized ccRCC. As you can see, looking here with people with specific RCC survival, patients with RCC tumors that have BAP1 positive tumors have significantly better survival outcomes than those who have BAP1 negative tumors, again with a Hazard Ratio of approximately 3.

Importantly, this test allows us to identify tumors that are simultaneously mutated for BAP1 and PBRM1. This is important.Slide A Slide B

(This slide in presented in two parts to help understand lecture.)
Upper half of slide showing stained pathology images.)

I am going to show you look at this tumor over here (upper left path image A) you can see that the tumor cells, there are some that have brown nuclei, but these are the endothelial and the stromal cells (along the edge of the white). The tumor cells are negative for BAP1.

This is the immunohistochemistry (upper right path image B) for PBRM1, where we find the same thing,where the tumor cells are negative for PBRM1.

Now (left path image C) compare these tumors with these images below. You can see here that the tumor cells positive for BAP1 in this area (the upper right corner of the path image C) and they are negative (in the lower left corner of Slide C), where you can see specific nuclei which look blue over there.

Now if you look at the parallel section (Lower right path slide D) you can see the area that was BAP1 positive (left hand side???D) is actually also PBRM1 negative, and the area which was BAP1 negative is actually PBRM1 positive.

So what you have over here (inthe upper slides A & B) is a tumor which has lost BAP1 and PBRM1 in the same tumor region, the same cells. The tumor has lost BAP1 and PBRM1 in independent regions. Obviously these tumors will be acting differently and the tumor we are most interested in is this tumor type (in the upper left image A).

You have seen in our immunohistochemistry test. We believe we can separate clear cell renal cell carcinoma into four different molecular subtypes. This is looking at Mayo registries, where the patients with best outcomes are those whose tumors are well-typed for PBRM1 and BAP1. Then you have 2) patients that have tumors which are deficient for PBRM1, 3) patients that have tumors that are deficient for BAP1, and 4) patients whose tumors are deficient for both. As you can see the Hazard Ratio is 1.3, 3.2 and 5.2, respectively.

As I mentioned to you at the outset, that these tumors were underrepresented and indeed in this very large cohort, we found a very large significant underrepresentation with 1.8% of the tumors being double mutant, compared to 5.3% (which would been expected) with a very highly significant p value, again indicating there is mutual exclusivity–for reasons we do not yet understand.

Importantly BAP1 and PBMR 1do not predict outcomes independently of SSIGN. SSIGN is the nomogram created by the Mayo Clinic, which is based on Stage, SIze, Grade, and Necrosis. This is the SSIGN nomogram; this is the independent validation. You can see the curves separate beautifully, depending upon the score.

Now another question I submit to you. Should nomograms trump biology? In other words, if they live the same, “What do I care?” That has been the traditionally the thinking in the clinic. But look at these animals. A bullfrog and a grizzly bear also live about 30 years. However, they’re very different. The same is true for cottonmouth, a beaver or hummingbird or a newt. So even though they live the same, they are actually quite different!

We should be probing deeper and in fact, they should be dealt with differently!

I believe that clear-cell renal cell carcinomas are in fact divided for at least four different subtypes. There are tumors that are wild type for both BAP1 and PBRM1, tumors that are PBRM1 deficient, tumors that are BAP1 deficient, and tumors that are deficient for both. In the future we are going to see different treatments for different tumor types.

In conclusion, the discovery of BAP1 and PBRM1 mutations in clear cell renal cell carcinoma, how they relate to each other, and how they affect outcomes establishes the foundation for the first molecular and functional classification of sporadic ccRCC.

These two genes define for distinct subtypes, which I just went over and you have the Hazard Ratios and p-values written down there. These two tumors are not only associated with different outcomes, but they are also associated with different activations on the mTOR1 pathway and gene expression. Finally we identify mutations in BAP1 which define a novel clear-cell renal cell carcinoma syndrome. I have forty seconds left!

I will go through these very quickly. Suffice it to say, we have also done molecular genetic analysis in non-clear-cell renal cell carcinoma, papillary, chromophobe, oncocytomas, This is now in press in Nature Genetics.

We found that papillary clear-cell carcinoma have more mutations than clear cell carcinoma, whereas chromophobe and oncocytomas have significantly lower mutation burdens, which is depicted there.

These are some genes we found overrepresented– five seconds! You can see the copy number alterations, gene expressions. Anyway, these papers will be coming out next week.

Finally, to acknowledge people who did the work in my laboratory, Pena-Llopis. We have had a close collaboration with the people at Mayo Clinic, and also the group at Genentech. We also work very closely with our surgeon and Payal Kapur, our pathologist.

We all want the cure, the Complete Response (CR) that can lasts many months or years. Often we have to settle for some reduction in our tumors or mets, a Partial Response (PR). But even “Stable Disease” is welcome news. To get that cancer back in its cage, even for a time, is better than “Progressive Disease”. When the cancer is progressing, your life may be regressing, and that isn’t what you want to hear. That Progression Free Survival (PFS) has to start with stopping the cancer.

As complete and durable (ten years) responder to high dose interleukin 2 (HD IL-2), I welcome any discussions of “Clinical Benefit (CB)”. CB includes all the good responses with any cancer treatment, CRs, PRs, and SDs. We and our doctors need this information to make informed decisions about treatment, for IL2 or other meds. The value of Stable Disease has been ignored in many studies. Maybe there are lessons here for you and your doctors, especially about the under-utilized HD IL2.

There are few new studies about the use of HD IL2 following the approval of the targeted therapies. The ease of use of these agents, along with the desire not to send patients to specialty centers for IL2, limited its use. It was difficult to select patients, and the CR and PRs were relatively small in number. Doctors often did not discuss the possibility of a cure with their patients. Did patients also miss the chance for Stable Disease, and with it, a “Clinical Benefit”?

Patients in this study who did not have a CR, but whose cancer stopped growing benefited. That CB was not counted in terms of the approval of the drug, nor do doctors consider it in their recommendations. Should this possibility be discussed with patients? Most patients would surely answer, “Yes!” to that question.

The researchers recognize of the value of Stable Disease (SD) as an outcome, versus only Complete Response (CR) or Partial Response (PR). The usual outcome measures, Progressive Free Survival (PFS), or Overall Survival (OS), are noted, as isTime to Next Treatment (TNT). TNT implicitly recognizes that a failed or limited response will likely be followed by another treatment. Early on, there were no subsequent treatments, sad to say.

The original clinical trial which led to FDA approval of HD IL2 recognized only CR, which was 5%, with the median not reached during the trial, and PR, which was 14%. Study footnotes indicate that three of the PRs had surgery which rendered them disease free at the time of the publication. This would now be called a “salvage therapy”, and put them in the No Evidence of Disease (NED) class. A different analysis of this data would have upped the CRs some small percentage, and some SD would also have been found.

Also the definition of PR was 50% or greater reduction in measurable tumor size, the sum of the perpendicular diameters of all lesions, with no new increase of sizeof any other mets. Far less strict measurements of PR were used in the targeted therapy trials, with a 30% tumor reduction defined as a Partial Response.

With those definitions in mind, note that there are CRs in 11% of patients, with a PR in an additional 6% of patients. Most important is the SD category, which was achieved for 31% of all patients. This total of 47% is described for the group as being of Clinical Benefit (CB). Certainly patients value the responses of SD, which seems to have provided slightly over one year versus 3-4 months benefit to those who did not have SD.

When comparing the value of Objective Response (OR) with its median of 1616 days to that of Stable Disease (SD) measured as 1476 days, one can clearly see the value of achieving Stable Disease. Unfortunately, those patients with Progressive Disease, or with responses Not Evaluable (NE), showed OS of 365 days.

Patients should be aware of these definitions and the impact the lack of parallel comparisons in making these critical decisions. Ten years ago, the patients reminded one another to stay alive until the next treatment. Having Stable Disease made that possible. Let’s apply the same tests to all the available treatments when making these life-changing choices of treatment.

Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB (OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2.

Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer.

Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table.

Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC patients. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling patients for treatment with HD IL-2.